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Phytochemical profiling and antioxidant potential of Daphne mucronata Royle and action against paracetamol-induced hepatotoxicity and nephrotoxicity in rabbits.

ABSTRACT: The paracetamol-induced injuries of liver and kidneys in animals are mostly used to screen out the hepato and nephroprotective effect of extract or other therapeutic agents. In the present study total phenolic and flavonoid contents, in vitro antioxidant, and in vivo hepato/nephroprotective (on paracetamol-induced intoxication in experimental rabbits) potentials of the Daphne mucronata leaves methanolic extract were determined. For the identification of possible phytochemicals, HPLC (high performance liquid chromatography) analysis was carried out and a total of eight phenolic compounds; malic acid, gallic acid, chlorogenic acid, epigallocatechin gallate, quercetin, morin, ellagic acid, and rutin were identified. D. mucronata extract at doses of 250 and 500 mg/kg body weight were given for eight days to paracetamol intoxicated rabbits and the observed results were compared with standard Silymarin. The level of liver enzymes like aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum triglyceride, serum cholesterol, serum bilirubin, and kidneys biomarkers like serum urea, uric acid, and creatinine, as well as lipid peroxidation malondialdehyde contents were increased while the antioxidant enzymes like reduced glutathione and total antioxidant capacity were decreased. Furthermore, histopathological analysis of the liver and kidney tissues of control and treated groups also confirmed the hepatoprotective and nephroprotective effect of the D. mucronata which was most probably due to its high antioxidant phenolic and flavonoid phytoconstituents.

SUBMITTER: Nazir N

PROVIDER: S-EPMC8381059 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeDaphne mucronata Royle grown in Iran has shown anticancer activities against different cancer cell lines. Therefore, within this study, we investigate the phytochemical pattern of this plant.MethodPhytochemical investigation was done using standard column chromatography system: The structures were recognized by the interpretation of one and two-dimensional nuclear magnetic resonance (NMR) spectra and the help of High-Resolution Electrospray Ionization Mass spectroscopy (HR-ESIMS) and Infrared spectroscopy (IR) data. Stereochemistry was determined using 2D and 3D NOESY, and comparison of coupling constant values with literature. The absolute configuration was determined and confirmed using specific rotation and electronic circular dichroism experiments. Cytotoxicity was done against HeLa cells by standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Luciferase assay was used to check if the compounds can inhibit the activation of cancer-related signaling pathways. Molecular docking simulation was done for biological activity evaluation and to examine the interaction of the ligand with each of the proteins.ResultsA new sesquiterpenoid, 4,11(12)-guiadiene-1-ol-3-one (4), together with eight specialized metabolites, betulinic acid (1), coniferyl aldehyde (2), oleanolic acid (3), daphnetoxin (5), apigenin (7), syringin (8), and genkwanol A (9) were isolated and reported for the first time from the shoots of the plant. Compound 4 as an undescribed compound was submitted for cytotoxicity assay and showed moderate activity with the IC50 value of 51.3 ± 4.2 μM against HeLa cancer cells. It showed selective inhibition of Interleukin-6 mediated signal transducer and activator of transcription 3 pathway (STAT-3/ IL-6), and Smad protein / transforming growth factor beta (TGF-β) transcription factors when screened through an array of cancer signaling pathways. Molecular docking confirmed biological tests and showed the interaction with STAT3 and Smad proteins.ConclusionAn undescribed sesquiterpenoid: 4,11(12)-guiadiene-1-ol-3-one in addition to eight known compounds were isolated. The new sesquiterpene was evaluated for the luciferase assay on 14 main cancer-related signaling pathways and showed selective inhibition of STAT3/IL6, and Smad/ TGF-β transcription factors. Molecular docking simulation showed more interactions with STAT3 than Smad, which confirms better interaction of compound 4 with STAT3 than Smad proteins. Graphical abstract.

Project description:Background and purposeParacetamol, a major cause of acute liver failure (ALF) represents a significant clinical problem. Adrenoceptor stimulation or antagonism can modulate chemical-induced hepatotoxicity. We investigated the role of endogenous catecholamines and alpha(1)-adrenoceptors in the development of paracetamol- induced hepatotoxicity.Experimental approachParacetamol (3.5 mmol kg(-1)) was administered to male CD-1 mice, with and without alpha(1)-adrenoceptor antagonists (prazosin, doxazosin, terazosin and tamsulosin; 35.7 micromol kg(-1)). Serum transaminases and hepatic glutathione (GSH) levels were assessed as markers of hepatic damage. Paracetamol bioactivation was assessed by covalent binding, hepatic and urinary conjugate formation and uridine glucuronosyltransferase activity. Plasma catecholamines levels and hepatic congestion were also analysed.Key resultsPlasma catecholamine levels were significantly elevated 5 h post paracetamol administration. Prazosin prevented hepatotoxicity when administered 1 h before a toxic paracetamol insult and importantly, when administered up to 1 h post paracetamol injection. Prazosin had no effect on paracetamol-induced depletion of hepatic GSH, paracetamol bioactivation or paracetamol-induced transcription of defence genes. Paracetamol toxicity is associated with marked accumulation of erythrocytes within hepatic sinusoids and prazosin completely prevented this accumulation.Conclusion and implicationsParacetamol-induced hepatocellular damage is associated with increased circulating catecholamines. alpha(1)-Adrenoceptor antagonists conferred complete protection from paracetamol -induced hepatotoxicity. Protection was associated with absence of hepatic erythrocyte accumulation. Increased catecholamine levels may contribute to the pathophysiology of paracetamol-induced hepatotoxicity by compromising hepatic perfusion. Protection against paracetamol toxicity by alpha(1) antagonists in mice has implications for therapeutic management of patients presenting with paracetamol overdose and ALF.

Project description:Our study was designed to screen the antibacterial potency of Princepia utilis leaf and seed extract and to measure their antioxidant effects, total phenol content, total flavonoid content, and total carbohydrate content. Collected samples were extracted by cold maceration. Hexane, ethyl acetate, methanol, and distilled water were used as extraction solvents. In the disc diffusion method, P. utilis ethyl acetate leaf extract was most prominent against Staphylococcus epidermis with a zone of inhibition (ZOI) of 13.83 mm. Similarly, methanolic leaf extract was most prominent against Staphylococcus aureus (ZOI-12.33 mm). Furthermore, the methanolic seed extract was most sensitive against Klebsiella pneumoniaee (ZOI-11.66 mm) Escherichia coli (ZOI-9.0 mm). The lowest minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 0.5 mg/mL and 0.6 mg/mL, respectively, were shown by ethyl acetate leaf extract against S. epidermis. Similarly, the highest values of MIC and MBC, i.e., 20.8 mg/mL and 33.3 mg/mL, respectively, were shown by hexane leaf extract against S. epidermidis. On the other hand, evaluation of antioxidant capacity revealed that ethyl acetate leaf extract showed the maximum antioxidant effect (IC50: 66.69 μg/mL). The total flavonoid contents of different extracts were measured in the range of 37 ± 0.74 μg QE/mg dry extract weight (methanolic seed extract) to 321.84 ± 4.82 μg QE/mg dry extract weight (hexane seed extract). Likewise, the total polyphenol content ranged from the hexane leaf extract (17.33 ± 0.642 μg GAE/mg dry extract weight) to ethyl acetate leaf extract (62.56 ± 1.284 μg GAE/mg dry extract weight). We found a variation in total carbohydrate content in the range of 23.55 ± 1.125 μg glucose/mg dry extract weight (hexane leaf extract) to 96.63 ± 2.253 μg glucose/mg dry extract weight (aqueous leaf extract). Overall, this study revealed that leaf and seed extract of P. utilis exhibited noteworthy antibacterial effects against diverse pathogenic microorganisms.

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Phytochemical profiling and antioxidant potential of Daphne mucronata Royle and action against paracetamol-induced hepatotoxicity and nephrotoxicity in rabbits.

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